Benzoylhaloalkanesulfonanilides

ABSTRACT

BENZOYLHALOALKANESULFONANILIDES OF THE GENERAL TYPE   1-(((Y)N,(RX-SO2-N(-R)-)PHENYL)-CO-),(Y)N&#39;&#39;-BENZENE   WHEREIN RX IS A HALOALKYL GROUP HAVING UP TO FOUR CARBON ATOMS AND AT LEAST ONE HALOGEN ATOM BONDED TO THE ALPHA CARBON ATOM OR IF THERE IS NO HALOGEN BONDED TO SAID ALPHA CARBON ATOM, HAVING AT LEAST 2 HALOGEN ATOMS BONDED TO THE BETA CARBON ATOM, R IS HYDROGEN, ALKYL OR ALKENYL CONTAINING NOT MORE THAN THREE CARBON ATOMS, OR A PHARMACEUTICALLY ACCEPTABLE CATION; EACH Y IS SELECTED FROM HYDROXY, HALOGEN AND ALKYL, ALKOXY, HALOALKYL AND HALOALKOXY GROUPS HAVING UP TO 4 CARBON ATOMS AND N AND N&#39;&#39; ARE EACH 0-3. THESE COMPOUNDS AND THEIR SALTS HAVE VALUABLE PHARMACOLOGICAL ACTIVITY AS ANTI-INFLAMMATORY AGENTS.

United States Patent 3,576,866 BENZOYLHALOALKANESULFONANILIDES Jerry E. Robertson, North Oaks, Joseph K. Harrington,

Edina, and Donald C. Kvam, North Oaks, Minn., assignors to Minnesota Mining and Manufacturing Company, St. Paul, Minn.

No Drawing. Continuation-impart of applications Ser. No. 588,338, Oct. 21, 1966, and Ser. No. 719,741, Apr. 8, 1968. This application June 12, 1969, Ser. No. 832,824

Int. Cl. C07c 143/74 U.S. Cl. 260-556 14 Claims ABSTRACT OF THE DISCLOSURE Benzoylhaloalkanesulfonanilides of the general type wherein R is a haloalkyl group having upto four carbon atoms and at least one halogen atom bonded to the alpha carbon atom or if there is no halogen bonded to said alpha carbon atom, having at least 2 halogen atoms bonded to the beta carbon atom, R is hydrogen, alkyl or a-lkenyl containing not more than three carbon atoms, or a pharmaceutically acceptable cation; each Y is selected from hydroxy, halogen and alkyl, alkoxy, haloalkyl and haloalkoxy groups having up to 4 carbon atoms and n and n are each 0-3. These compounds and their salts have valuable pharmacological activity as anti-inflammatory agents.

This application is a continuation-in-part of the copending applications Ser. No. 588,338, filed Oct. 21, 1966 and now abandoned, and Ser. No. 719,741, filed Apr. 8, 1968.

The invention relates to haloalkanesulfonanilides which have valuable pharmacological activity. Steroids having cortisone-like activity have heretofore been used for treatment of inflammatory, e.g. arthritic conditions. While these are effective, they have certain undesirable side effects. Consequently, there is a need for effective anti-inflammatory agents which are free of such disadvantages.

The novel and efiicacious compounds of the present invention are non-steroidal in character, and their use does not entail side elfects peculiar to steroid therapy. Of particular value in the anti-inflammatory compounds of the present invention is their relatively low toxicity, and they are well-tolerated by the gastrointestinal tract. A number of the new compounds also have anti-pyretic and analgesic activity. The pharmacological activities of these compounds have been elucidated by means of mammalian animal tests.

The present invention contemplates providing a novel class of pharmacologically active compounds, especially compounds with anti-inflammatory activity. The invention further aims to provide compositions of the novel, active compounds which are suitable for administration for pharmacological purposes. Within the purview of the invention are processes for the preparation and use of the compounds of the invention for pharmacological purposes. Still other objectives of the invention will become apparent to those skilled in the art from reading the following disclosure.

3,576,865 Patented Apr. 27, 1971 Formula I wherein R is a haloalkyl group having up to four carbon atoms and at least one halogen atom bonded to the alpha carbon atom or if there is no halogen bonded to said alpha carbon atom, having at least 2 halogen atoms bonded to the beta carbon atom, R is hydrogen, alkyl or alkenyl containing not more than three carbon atoms, or a pharmaceutically acceptable cation; each Y is selected from hydroXy, halogen and alkyl, alkoxy, haloalkyl and haloalkoxy groups having up to 4 carbon atoms and n and n are each 0-3.

Unless otherwise specified, in the compounds of the invention, the various halogen atoms in an R group can be the same or different, the various Y groups can be the same or different (regardless of whether they occur as substituents on the same ring or on the two different rings) and n and n' can be the same or different. When n and n are both zero, the rings will be unsubstituted, i.e. the compounds will have the formulae:

t RXSOZN 0 wherein the halogen therein is all fluorine (especially compounds in which R is HCF or H CF). The compounds in which R is perfluorinated also form a preferred group, particularly trifiuoromethyl.

Preferably in the foregoing groups and other compounds of the invention, the haloalkylsulfonamido group in the compounds of the invention is oriented meta to the carbonyl group.

The compounds in which n and n are zero, or in which one of them is zero and the other is one and the Y or Y is hydroxy have outstanding anti-inflammatory activity and therefore also form a preferred class.

When R is alkyl, it is preferred that R is methyl or ethyl. When Y and/or Y are alkyl or alkoxy, it is preferred that the alkyl and alkoxy groups contain one carbon atom. Similarly when Y and/or Y are haloalkyl or haloalkoxy, it is preferred that they contain one carbon atom.

The products of the present invention are effective antiinflammatory agents and some also are analgesic and antipyretic agents. The anti-inflammatory activity can be conveniently demonstrated using assays designed to test the ability of these compounds to antagonize the local edema which is a characteristic of the anti-inflammatory response (rat foot edema test) and to inhibit the onset of the erythematous manifestation of inflammation (guinea pig erythema test).

The edema test is performed on adult female rats. One group of 10 rats serves as non-medicated controls, while another group of 10 rats receives the test compound at various times prior to the induction of the edema, usually minutes, one hour and/ or 18 hours. The test compound is administered as a suspension in 4 percent aqueous solution of acacia. Edema is induced by the plantar injection of 0.5 percent carrageenin (0.1 ml./foot) into the right hind foot. The left hind foot receives a like volume of 0.9 percent saline solution. One hour later, the volume of each hind foot is determined plethysmographically. The edema is expressed as the increase in the volume of the edemogen injected foot (volume of the edemogen foot less the volume of the saline foot). The present inhibition is calculated by dividing the mean increase in the edema of the edemogen foot of the medicated group by the mean increase in the non-medicated group, multiplied by 100. An active dose is that giving a statistically significant inhibition of the induced edema, usually about 30-35 percent inhibition.

Leading references to this method are:

(l) Adamkiewicz et al., Canad. J. Biochem. Physio. 33:

(2) Selye, Brit. Med. J. 2: 1129, 1949; and

(3) Winter, Proc. Soc. Exper. Biol. Med. 111: 544, 1962.

The erythema test is performed on adult, albino guinea pigs of either sex weighing 400-600 g. Hair is removed from the abdomen of the animals by a depilatory mixture the afternoon of the day prior to the day on which they are to be used. One group of 5 animals serves as nonmedicated controls, while another group of 5 receives the test compound 30 minutes prior to direct exposure to ultraviolet light. For induction of arythema, the animal is restrained on a small animal board. Three circular sections (6-8 mm. in diameter) of the ventrolateral abdominal area of the animal are then exposed to a controlled amount of ultraviolet radiation. Two hours after exposure, the erythema is scored 05 on the basis of its intensity and completeness (full or partial circles). The maximal score per animal is 15. The percent inhibition is calculated on the basis of the mean score for the medicated group versus the non-medicated group. An active dose is taken to be that giving a statistically significant inhibition of the induced erythema, usually 35-40 percent inhibition. Modifications of this test include variation in the time and method of drug administration.

Leading references to this method are:

(1) Wilhelm, Schweiz. Med. Wschr. 25: 577, 1949, and (2) Winder et al., Arch. Int. Pharmacodyn. 116: 261,

In the rat foot edema test and/or the guinea pig erythema test, the following compounds have been found to be effective anti-inflammatory agents (i.e., to have significant activity) at dosage levels of 100 mg./kg. or less in single doses:

3-benzoyldifiuoromethanesulfonanilide,

3-benzoyldifluoromethanesulfonanilide, sodium salt,

3-benzoyl-4-hydroxytrifiuoromethanesulfonanilide,

3-benzoylfluoromethanesulfonanilide,

3- 4-chloro-2-methylb enzoyl) trifluororneth anesulfonannilide,

N-methyl-3 -benzoyltrifiuoromethanesulfonanilide,

N-ethyl-3-benzoyltrifl uorometh anesulfonanilide,

3- (4-methylbenzoyl fiuoromethanesulfonanilide,

4- (4-chlorobenzoyl difiuo romethanesulfonanilide,

3-benzoyl-2,2,2-trifiuoroethanesulfonanilide,

3- 4-methoxybenzoyl difiuoromethanesulfonanilide,

3- (4-methoxybenzoyl fiuoromethanesulfonanilide,

4-benzoyldifluoromethanesulfonanilide,

3- Z-hydroxybenzoyl trifluoromethanesulfonanilide,

3-benzoyltrifiuoromethanesulfonanilide,

4-benzoyltrifiuoromethanesulfonanilide,

3-(4-methylbenzoyl trifluoromethanesulfonanilide,

3- (4-methoxybenzoyl) trifl uoromethanesulfonanilide,

3- 4-chlorobenzoyl trifl uorometh anesulfonanilide,

3- 3-chlorobenzoyl trifiuoromethanesulfonanilide,

3- 2-chlorobenzoyl trifiuoromethanesulfonanilide,

3- Z-methylbenzoyl trifiuoromethanesulfonanilide,

3-benzoylperfluoroethanesulfonanilide,

3 (4-fluorobenzoyl) trifluoromethanesulfonanilide,

3 -benZoyl-4-chlorotriflu oromethanesulfonanilide,

3 -benzoyl- 2-hydroperfiuoroethane sulfonanilide,

3 -benzoyl-4-chlorodifluoromethanesulfonanilide,

4-chloro-3- (4-chlorobenzoyl) trifiuoromethanesulfonanilide,

4-chloro-3- 4-fluorobenzoyl) trifluoromethanesulfonanilide,

3- 4-fluorobenzoyl difluoromethanesulfonanilide,

3-benzoylchloromethanesulfonanilide,

4-chloro-3 (4-fiuorobenzoyl difiuoromethanesulfon anilide, and

4-chloro-3- 4-chlorobenzoyl) difluoromethanesulfonanilide.

Aspirin, which is very widely used as an anti-infiamatory agent, is only marginally active at mg./kg. in the rat foot edema test.

The compounds named hereinabove, and their salts are made by the general process described hereinbelow and as further specifically illustrated in the examples.

To produce the compounds of Formula I, wherein R is hydrogen, an aminobenzophenone is condensed with a haloalkylsulfonyl halide or anhydride according to the following scheme:

II 0 NH; O axsozx i 0 ll msolNn BK Ya Ya wherein R n, n and Y are as previously defined and X represents a halogen atom, preferably chlorine or fluorine, or the corresponding anhydride grouping -OSO R (R being defined as above). Approximately equivalent amounts of the reactants are brought together at temperatures most often ranging between about 15 and 150 C. If necessary or desirable, the reaction can be carried out in a pressure vessel. The reaction is preferably, but not necessarily, carried out in the presence of an acid acceptor such as the alkali or alkaline earth metal carbonates and bicarbonates or a tertiary amine such as pyridine, triethylamine or N,N-dimethylaniline. The amount of the acid acceptor can be varied widely; however, a 10 mole percent excess of that amount of base sufficient to bind the liberated strong acid (HX) is routinely employed.

The condensation is usually conducted in the presence of an appropriate inert organic solvent. Typical solvents suitable for this purpose are methylene chloride, chloroform, carbon tetrachloride, benzene, toluene, bis(2-methoxyethyl) ether, acetonitrile, nitromethane, and the like.

After reaction is complete, if the reaction solvent is not water miscible, the product mixture can be extracted with a dilute aqueous base solution. The product, in the form of a salt which is usually soluble in the aqueous layer, is precipitated therefrom by addition of a mineral acid such as hydrochloric or sulfuric acid, and collected by filtration. Alternatively the product mixture can be washed with aqueous hydrochloric acid, the solvent evaporated in vacuo, and the residue dissolved in a dilute aqueous base solution which is Washed with dichloromethane and treated with decoloriziug charcoal. The product, in the form of a salt is then isolated as described above.

If the reaction solvent is Water miscible, the product is generally obtained by dilution of the reaction mixture with water. The product, a solid or oil, is separated and purified by conventional methods. The compounds prepared according to the foregoing procedures are crystalline solids purified, in general, by recrystallization from aqueous alcohol, trichloroethylene, hexane, benzene-hexane mixtures and the like. Elution chromatography has also been found to be a useful purification technique.

. An additional and preferred method of obtaining the compounds of the invention in which Y is hydroxy is by cleavage of the alkoxy group of the comparable sulfonanilides in which Y is alkoxy. This can be done conveniently with hydrogen iodide-acetic acid mixtures. Alternatively, other known ether cleavage methods, e.g. hydrobromic acid-acetic acid, may be used.

When R is hydrogen in the compounds of the invention, this hydrogen is acidic in nature. Consequently, they readily form salts of alkali metals, alkaline earth metals, amines and the like. Pharmaceutically acceptable salts of these acidic compounds are included within the scope of Formula I, when R is a pharmaceutically acceptable cation.

Many of the salts are readily prepared by adding the stoichiometric amount of the selected base in inert solvent solution to the acidic compound. The resulting solution is treated to remove the solvent, e.g. by evaporation under reduced pressure. The salts are conveniently used in making pharmaceutical preparations for administration of the compounds, e.g. in capsules for oral administration. Another method for the preparation of salts of the invention is the reaction of a salt of the invention with an organic or inorganic salt in a cation exchange reaction.

Compounds of the invention wherein R is alkyl or alkenyl are readily prepared by the reaction of the compounds of the invention where R is hydrogen or a cation with an alkyl or alkenyl halide. This method for alkylation is known to the art.

Suitable haloalkanesulfonylanhydrides and halides (e.g. chlorides and fluorides) for use as starting materials in these procedures are known to the art, for example:

fiuoromethanesulfonyl chloride, fluorochloromethanesulfonyl chloride, difluoromethanesulfonyl chloride, dichloromethanesulfonyl chloride, 2,2,2-trifluoroethanesulfony1 chloride, trifluoromethanesulfonyl chloride, 1,1,2,Z-tetrafluoroethanesulfonyl chloride, bromomethanesulfonyl chloride, 2,2,3,3-tetrafluoropropanesulfonyl chloride, Z-hydroperfluoropropanesulfonyl chloride,

and many others disclosed e.g. in U.S. Pat. 2,732,398.

The aminobenzophenones used in producing the compounds of the invention are generally described in the chemical literature or can be prepared from corresponding known substituted nitrobenzophenones by reduction. Any nitrobenzophenones or aminobenzophenones not specifically disclosed in the chemical literature are prepared by methods known in the literature for analogous compounds. Exemplary of such starting materials are:

-amino-2-chlorobenzophenone, 3-amino-4-fluorobenzophenone, 3-amino-5-bromobenzophenone, 3-amino-4'-ethylbenzophenone, 3-amino2-ethoxybenzophenone, 3-amino-4-ethoxybenzophenone, etc.

The following examples are given for the purpose of further illustrating the present invention, but are not intended to limit the scope thereof. All melting and boiling points are uncorrected. All parts are by weight unless otherwise specified in the examples.

EXAMPLE 1 Preparation of 3-benzoylfluoromethanesulfonanilide A 500 ml. flask fitted with reflux condenser was charged with 8.7 g. of N,N-dimethylaniline (0.72 mole), a solution of 12.8 of 3-aminobenzophenone (0.065 mole) in ml. of methylene chloride, 8.6 g. of fluoromethanesulfonyl chloride (0.065 mole, B.P. 138141 C.) and 200 ml. of methylene chloride. The mixture was heated at reflux temperature overnight, then cooled, washed twice with 500 ml. portions of 10 percent hydrochloric acid and dried over anhydous magnesium sulfate. The solvent was removed by evaporation leaving an oil that crystallized after 3 hours in the vacuum oven to alford relatively pure product, M.P. 116-119 C. This solid was taken up in 300 ml. of 10 percent aqueous sodium hydroxide. The solution was warmed, treated with activated carbon and acidified to pH 1 with concentrated hydrochloric acid. An oil formed initially but crystallized to give a solid, M.P. 115-117" C. This was recrystallized from 95 percent ethanol to give analytically pure product, M.P. 117-120 C.

Analysis.--Calculated for C H FNO S (percent): C, 57.3; H, 4.1. Found (percent): C, 57.7; H, 4.1.

EXAMPLE 2 Preparation of 3-benzoyldifluoromethanesulfonanilide A one liter flask fitted with reflux condenser was charged with 0.1 mole of 3-aminobenzophenone, 10 ml. of pyridine, 0.1 mole of difluoromethanesulfonyl chloride, and 400 ml. of benzene. The mixture was heated at 50-55 C. for 72 hours and then extracted with 10 percent aqueous sodium hydroxide. Acidification of the alkaline layer produced 'a solid which was recrystallized from trichloroethylene-hexane mixtures to aflord analytically pure product, M.P. 99-1005 C.

Analysis.Calculated for C H F NO S (percent): C, 54.1; H, 3.6; N, 4.4. Found (percent): C, 53.9; H, 3.6; N, 4.4.

EXAMPLES 3-32 By the use of the general procedure of Examples 1 and 2 and the substitution of other haloalkanesulfonyl chlorides and other substituted aminobenzophenone starting materials, all of which are known, the following exemplary compounds are obtained:

M.P 0 Ex. (unoor: No. reeted 3 2-benzoyldiflu0romethanesulfonanilide 79. 5-8 4 3-(4-1nethylbenz0yl)difluoromethanesulionanilide 119-121 5. 3-(4-chlorobenzoyl) difluoromethanesulfonanilide. 127-129 6 S-(A-methoxybenzoyl)fluoromethanesulfonanilide. 116. 5-118. 5 7 3-benzoyl-4-chlor0difl uoromethanesulfonanilide 99-102 8 3-benzoyl-4-chlorofiuoromethanesulfonanilide 113-116 9. tbenzoyldifluoromethanesulfonanilide 124. 5-126. 5 10. 2-benz0ylfluoromethauesulfonanilide 74. 5-75. 5 11 3-(4-chl01obenzoyl)fluoromethanesulfonanilid 118-120 12 3-(4-n-butoxybenzoyl)fluoromethanesulfonanili 113-117 13 3-(4-t-butylbenzoyl) fluoromethanesulfonanilide 102-105 14 3- (4-fiu01'obenz oyl) difluoromethanesulfonanilide 8 15 3-(4-fiuorobenzoyl)fluoromethanesulfonanilide 127-129. 5

16 3-(4-l1ydroxybenzoyl) difluoromethanesulfonanilide 150-152 17 2-benzoyl-4-ehlorodifl uoromethanesulfonanilide 98-100 18- 2-benzoyl-4-chl0rofluoromethanesulfonanilide 88-89. 5 19 3-benz oyl (2hydroperfiuoroeth ane) sulfonanilide -80. 5 20 3-benzoyl-(2hydroperfiuoro-n-propane) sulfonanil e. 94-96 21 3-benzoylehloromethanesulfonanilide -97 22 4-chl0ro-3- t-fiuorobenzoyl) difluorometh ane- 101-103 sulfonanilide. 23 4=-el1l01'0-3-(4-methylbenzoyl) difluorometh ane- 77-79 sulfonanilide. 24- 4-ehloro-3- (4-ehlorobenzoyl) difluoromethane- 81-83 sulfonanilide. 25 3-benzoyl-4-ehlor0chloromethanesulfonanilide -133 26.- 3- i-methylbenzoyl) ehloromethanesulfonanili de 118-119 27 3-(2-methylbenzoyl) chloromethanesulfonanilide 88-89 28 3- (Z-methylbenzoyl) fiuoromethanesulfonanilide 101-102 29 3-(2-chlorobenzoyl) ch10romethanesulfonanilide 99-101 30- 3-(2-chlorobenzoyl) fluoromethanesulfonanilide. 123-125 31 3- (tchlorobenzoyl) ehlorome thanesulfonanilide 149-150 32 3-benzoylperfiuoro-n-butanesulfonanilide Prepared by the method of Example 84 from the compound of Example 34.

2 B.P. 186 C./0.00 mm.

EXAMPLE 33 Preparation of the sodium salt of 3-benzoyldifluoromethanesulfonanilide To a solution of 12.21 g. of reagent grade sodium hydroxide (0.305 mole) in 300 m1. of water were added 95 g. of 3-benzoyldifluoromethanesulfonanilide (0.305 mole). The mixture was stirred until dissolution was complete and the solution had pH 7.2 (sensitive pH paper). Water was removed to give a yellow solid which was taken up in about 200 ml. of glyme and treated with activated charcoal. The clear solution was then added dropwise with vigorous stirring to 5 liters of ethyl ether. The crystalline salt was isolated by filtration, washed with 4 liters of ethyl ether and driedto give analytically pure product, M.P. (dec.) 235 C.

Analysis.Calculated for C H F NaNO S (percent) C, 50.45; H, 3.05. Found: (percent): C, 50.6; H, 3.2.

Other salts are made by the same process, substituting other alkali or alkaline earth metal hydroxide for sodium hydroxide. Amine salts are made using alcohol solutions of the stoichiometric amount of the amine, in a similar manner, e.g. the dimethylaminoethanol salt. Alternatively, water solutions of the amine may be used.

EXAMPLE 34 Preparation of 3-(4-methoxybenzoyl)difluoromethanesulfonanilide A one liter flask fitted with reflux condenser was charged with 56.8 g. of 3-amino-4-methoxybenzophenone (0.25 mole), 26.5 g. of N,N-dimethylaniline (0.30 mole), 37.8 g. of difluoromethanesulfonyl chloride (0.25 mole) and 350 ml. of methylene chloride. The mixture was heated at reflux temperature for 36 hours and then was extracted with dilute aqueous sodium hydroxide. After treatment with charcoal, acidification of the alkaline extract afforded a solid which was washed with hot heptane and recrystallized from carbon tetrachloridehexane mixtures to afford analytically pure product, M.P. 118-120 C.

Analysis.-'Calculated for C H F NO S (percent): C, 52.8; H, 3.9; N, 4.1. Found (percent): C, 52.6; H, 3.9; N, 4.2.

EXAMPLE 35 Preparation of 3-benzoyl-2,2,2-trifluoromethanesulfonanilide A one liter flask was charged with 29.6 g. of 3-aminobenzophenone (0.15 mole), 9.2 g. of 2,2,2-trifluoroethanesulfonyl chloride (0.05 mole) and 250 ml. of methylene chloride. The mixture was allowed to stand for about an hour with occasional shaking. The reaction mixture was then washed with dilute hydrochloride acid to remove excess 3-aminobenzophenone, and the solvent was removed by evaporation to afford a solid product. Recrystallization of the solid from trichloroethylene and drying gave analytically pure product, M.P. 105 .5107 C.

Analysis.Calculated for C H F NO S (percent): C, 52.5; H, 3.5; N, 4.1. Found (percent): C, 52.7; H, 3.7; N,

EXAMPLE 36 Preparation of 3-(4-methoxybenzoyl)difluoromethanesulfonanilide A 500 ml. flask fitted with reflux condenser was charged with 10.5 g. of 3-amino-4'-methylbenzophenone (0.03 mole), 6.7 g. of N,N-dimethylaniline (0.055 mole), 6.6 g. of fluoromethanesulfonyl chloride (0.05 mole) and 150 ml. of methylene chloride. The reaction mixture was heated at reflux temperature for hours. Methylene chloride was then removed by evaporation, and the residue was extracted with dilute aqueous sodium hydroxide. The alkaline extract was washed with ethyl ether, treated with charcoal and acidified. The precipitated solid was recrystal lized from ethanol-water mixtures to give analytically pure product, M.P. 118-120 C.

Analysis.-Calculated for C H FNO S (percent): C, 58.7; H, 4.6; N, 4.6. Found (percent): C, 58.8; H, 4.8; N, 4.5.

8 EXAMPLE 37 Preparation of 3-benzoylperfluoroethanesulfonanilide A 300 ml. Parr pressure vessel was charged with 9.85 g. of 3-aminobenzophenone (0.05 mole), 150 ml. of triethylamine and 10.1 g. of perfluoroethanesulfonyl fluoride (0.05 mole). The mixture was heated at -100 C. for 24 hours.

Triethylamine Was removed by evaporation, yielding an oil which was taken up in benzene. The benzene solution was washed with dilute hydrochloric acid and extracted with dilute sodium hydroxide. Acidification with hydrochloric acid affords a solid which was recrystallized from ethanol-water to give white, solid product, M.P. -97 C.

Analysis.-Calculated for C H F NO S (percent): C, 47.5; H, 2.7; N, 3.7. Found (percent): C, 47.7; H, 2.8; N, 3.7.

EXAMPLES 38-42 By the use of the general procedures of Examples 34-37 and the substitution of other haloalkanesulfonyl anhydride and halide starting materials, the following exemplary compounds are obtained.

Example No.:

38 3-benzoylfluorochloromethanesulfonanilide.

39 3-benzoyl-l,1,3-trihydroperfluoropropanesulfonanilide.

40 3-benzoyldichloromethanesulfonanilide.

41 3-benzoyl-perfluoroisopropanesulfonanilide.

42 3-benzoylbromomethanesulfonanilide.

EXAMPLE 43 Preparation of 3-benzoyltrifluoromethanesulfonanilide Into a 3-necked, one liter flask equipped with stirrer, condenser, addition funnel, internal thermometer and nitrogen sweep were charged 59.8 g. of 3-aminobenzophenone (0.304 mole), 50.4 ml. of triethylamine and 400 ml. of chloroform. Trifluoromethanesulfonic anhydride was added slowly to the stirred mixture at 10-25 C. (ice-bath cooling). After stirring at room temperature for two hours, the solution was washed with dilute hydrochloric acid and then extracted with 10 percent aqueous sodium hydroxide. The aqueous extract was washed with chloroform until the washes were clear, clarified with charcoal, and acidified to pH 1 with concentrated hydrochloric acid. The product was collected by filtration, washed with water and dried. Recrystallization from hexane afforded analytically pure product, M.P. 99-101 C.

Analysis.Calculated for C H F NO S (percent): C, 51.1; H, 3.1. Found (percent): C, 51.3; H, 3.2.

EXAMPLES 44-83 By use of the procedure of Example 43 and the substitution of other, aminobenzophenone starting materials, the following exemplary compounds were obtained:

46- 3-(4-methylbenzoyl) trifiuoromethanesulfonanilide 129. 5-131. 5 47- 3-(4-methoxybenzoyl)trifluoromethanesulfonanilidm 122. 5-124. 5 48- 3- (a-fluorobenzoyl) trifluoromethanesulfonanilide 134-136 49 8- (4-chlorobenzoyl) trifluoromethanesulionanilide 123. 5-125. 5

50- 5-benzoyl-2-chlorotrifluoromethanesulfonanilide 102-103 51 3-benzoyl-5-ohlorotrifluoromethanesulfonanilide 114-116 52- 3-benzoyl-et-ehl0ro triflnoromethanesulionanilide 106-108 53 3-benzoyl-2-ehlorot1ifl uoromethanesnlfonanilide 92- 54. 4-(2-ehlorobenzoyl)trifluoromethanesulfonanilide 1144. 5-146. 5 55- 4-(3-chlorobenzoyl) trifluoromethanesulfonanilide 139-1 56 4-( 1-chlorobenzoyl) trifl uoromethanesulfonanilide -147 57 3-benzoyl-2-methylt1ifl uoromethanesulfonanilide 119-121 58- 5-benzoyl-2-niethyltrifluoromethanesulfonanilide 84-85 50- 3-benzoyl-5-methylt1ifl uoromethanesulfonanilide 94-06 00. 3- (3-methylbenzoyl) trifluoromethanesulionanilide 91-93 (11. 2-(3-me thylbenzoyl) trifluoromethanesulfonanilide- 92-03 Ex. (uncor- No. rected) 62 3- (2,5-dimethoxybenzoy1) trifiuoro- 121. 5-124 methanesulfonanilide.

63. 4-ehloro-3-(4-methylbenzoyl)trifiuoro- 88-90 methanesulionanilide.

64- 4-ch1oro-3-(4-n1ethoxybenzoyl)tiifluoro- 80-90 methanesulfonanilide.

65- 4-chlor0-3-(4-ohlorobenzoy1) trifiuoro- 82-83 methanesulfonanilide.

67- 3-(2-methylbenzoyl) tiitlnorornethanesulfonanillde 92-93 68- 4-chl01'o-2- (Z-ehlorobenzoyl) tritluoro- 86-88 methanesulfonanilide.

69 3- (3,4-dichlorbenzoyDtrifluoro- 146-147 methanesulfonanilide.

70- 3- (2,5-dimethylbenzoy1) trifl uoro- 85-86 methansulfonanilide.

71- 3-(2,3-di;rnethylbenzoyl)trifiuoro- 107-109 me thanesulfonanilide.

72 3-benzoyl-4-methoxytrifluoromethanesulfonanilide. 131-132 73 3-(2-methoxybenzoyl) trifiuoromethanesulfonanilide 87-89 74- 3- (2,6-dirnethylbenz0yl) trifluoro- 113-114 methanesulfonanilide.

75. 3-(4-chloro-Z-methylbenzoyl)tiifluoro- 135-137 methanesulfonanilide.

7 6. -benzoyl-2-methoxytiifiuoromethanesulfonanilide. 87-89 77 3-benzoyl-4-brornotrifluoromethanesulfonanilide 131 78- 3- (3,4-dimethylbenzoyl) trifluoro- 129 methanesulfonanilide.

79- 3-(2,4dirnethylbenzoyl)trifiuoro- 106-108 methanesulfonanilide.

80- 3-(4-ethylbenzoy1) tnfluoromethanesulfonanilide 90-91 3-(3-fluorobenz0y1)trifluoromethanesulfonanilide 96-98 82- 3-1)enzoyl-2-methoxytrifluoromethanesnlfonanilide 132-133 83 3-benzoyl-5-methoxytriflnoromethanesulfonanilide 89-91 EXAMPLE 84 Preparation of 3-benzoyl-4-hydroxytr1fiuoromethanesulfonanihde EXAMPLES 85-90 By use of the general procedure of Example 84 and the substitution of other benzoylmethoxysulfonanilides, the following exemplary compounds were obtained:

Melting Ex: point; No. (in C 85 3-(4-hydroxybenzoyl) tnfiuoromethanesulionanilide 156-158 86 3-(3-hydroxybenzoyl) trifiuoromethanesulfonanilide 169-172 5-b enzoyl-2-hydroxytrlfiuoromethanesulfonanilide. 178-181 88- 3-benz0yl-5-hydroxytiifluoromethanesulfonanili de 128-130 89 3-benzoyl-2-hydroxytrifiuoromethanesulfonanilide 86-88 90 3-(2-hydroxybenzoyl) trifluoromethanesulfonanilide. 131-133 EXAMPLE 9 1 Preparation of N-ethyl-3 -benzoyltrifluoromethanesulfonanilide Sodium carbonate (6.89 g., 0.082 mole) was dissolved in distilled water (70 m1.) and 3-benzoyltrifluoromethanesulfonanilide (27.0 g., 0.082 mole) was added in small portions. Water (30 ml. was added and the solution was stirred for three hours. The solution was filtered and the filtrate was evaporated to dryness in vacuo. The solid was dissolved in ethanol, treated with decolorizing charcoal and filtered. The filtrate was evaporated to dryness in vacuo, and the solid sodium 3-benzoyltrifluoromethanesulfonanilide was dried.

Analysis.Calculated for C14H9F3NNaO3S (percent): C, 48.0; H, 2.16. Found (percent): C. 48.0; H, 2.8.

Sodium 3-benzoyltrifluoromethanesulfonanilide (20 g., 57 mmole), acetone (250 ml.) and ethyl iodide (11.7 g., 75 mmole) 1 day. The reaction mixture Was evaporated to remove solvent and the oil obtained was dissolved in chloroform. The solution was washed twice with 10 percent sodium hydroxide, twice with water and dried over magnesium sulfate; then treated with decolorizing charcoal and filtered. The solvent was removed in vacuo and the liquid product was distilled through a molecular still to give a light yellow liquid, N-ethy-3-benzoyltrifluoromethanesulfonanilide, column temperature 170 C., pressure 1x10 mm. of mercury.

Analysis.Calculated for C H F NO S (percent): C, 53.8; H, 3.95. Found (percent): C, 53.8; H, 4.0.

EXAMPLES 92-101 By the use of the general procedure of Example 91 and the substitution of other reactive alkyl halides or dialkyl sulfates the following exemplary compounds are obtained:

Example No.:

Additional compounds of the invention prepared by the foregoing general procedures are as follows:

Melting Ex. point No. (in C.)

102. 3-(3-triflu0romethy1benzoyl) ttifluoromethanesul- 86-88 fonanilide.

103- 3-(ZtnQpipImmeth lbenmyI) trifiuoromethanesul- -111 nam e.

104. 3-(4-trlfluoromethoxybenzoyl) trifiuoromethanesul- 107-109 fonanihde.

What is claimed is: 1. A compound of the formula:

wherein R is a haloalkyl group having up to four carbon atoms and at least one halogen atom bonded to the alpha carbon atom or if there is no halogen bonded to said alpha carbon atom, having at least 2 halogen atoms bonded to the beta carbon atom, R is hydrogen, alkyl or alkenyl containing not more than three carbon atoms, or a pharmaceutically acceptable cation; each Y is selected from hydroxy, halogen and alkyl, alkoxy, haloalkyl and haloalkoxy groups having up to 4 carbon atoms and n and n are each 0-3. 1

2. A compound according to claim 1 wherein the halogen atoms in the R group are all fluorine.

3. A compound according to claim 2 wherein R is a perfluoroalkyl group.

4. N-methyl 3-benzoyltrifiuoromethanesulfonanilide according to claim 3. I I p 5. 3-benzoyl 4 -"hydroxytrifluoromethanesulfouanilide according to claim 3.

6. A compound according to claim 1, in which'the haloalkanesulfonamido group is in meta orientation to the carbonyl group.

7. A compound according to claim 6, in which R is HCF p 8. 3-benzoyldifluorornethanesulfonanilide according to claim 7.

9. The sodium salt of 3-benzoyldifluoromethanesulfonanilide according to claim 7.

10. A compound according to claim 6, in which R is H CF.

11. 3-benzoylfluoromethanesulfonanilide according to claim 10.

12. A compound of the formula:

a Ya wherein R is a haloalkyl group having up to two carbon atoms and at least one halogen atom bonded to the alpha carbon atom or if there is no halogen bonded to said alpha carbon atom, having at least two halogen atoms 14. A compound according to claim 2 wherein R is trifiuoromethyl.

References Cited UNITED STATES PATENTS 3/1937 Salzberg et a1 424250 OTHER REFERENCES Annali di Chimica, V01. 56(6), June 1966, p. 733, Rossi et a1.

HENRY R. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2, 576,866

Dated April 27, 1971 v n fl XIERRY ROBERTSON, JOSEPH K. HARRINGTON and DONALD C. KVAM It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 3 line 11 "present" should be --percent-- Column 3 line 31 "arythema" should be erythema- Column 3 line 60 "fonannilide" should be --fonani1ide- Column 3 line 6 t-( should be --3-( l- Column 6 line 1 "12.8" should be -12.8 g.

Column 7 line 14 "hydroxide" should be --hydroxides-- Column 7 line #8 "hydrochloride" should be --hydrochloric Column 7, lines 59-60 should read --Preparation of 3-( lmethylbenzoyl )fluoromethanesulionanilide-- Column 9 line 67 (30 m1. should be --(30 ml.

Column 10 line 3 following "75 mole)" insert -were heat to reflux and maintained at reflux temperature Column 10 line 10 "Nethy-3-" should be --N-ethyl-3- Signed and sealed this 16th day of November 1971 (SEAL) Atteat:

EDWARD H.FLETCHER,JR. Attesting Officer ROBERT GO'I'TSCHALK Acting Commissioner of Pat 

